EDITION AND MODIFICATION OF RNA FROM EUKARYOTIC CELLS AND VIRUSES BY ENZYMATIC DEAMINATION OF ADENOSINE TO INOSINE

The presence of inosine in the anticodon of several transfer RNAs (tRNA) of eukaryotic cells has been known for a long time. Recent work has now demonstrated that inosine is present in other RNAs, namely in the coding region of messenger RNA for the glutamate receptor (GluR mRNA) of mammalian brain, in the non-coding RNA transcript (TAR domain) of immunodeficiency Virus type HIV-1, and in the double-stranded regions of eukaryotic mRNA associated with antisense oligonucleotides (dsRNA). It is likely that inosine is also present in the primary replicative transcripts of certain viruses (measles virus). These inosine residues are produced by specific nuclear RNA deaminases. These newly discovered enzymes catalyze the hydrolytic deamination of selected adenosines during the complex process of RNA maturation (post-transcriptional events). In cytoplasmic mRNA and in viral RNA, inosine behaves like guanosine in subsequent transcription and ,translation! processes, leading to alteration of the DNA coded genetic information (editing). In tRNA, inosine in the first anticodon position restricts the pairing with the third base in mRNA codons to U, C and A, while inosine (its methylated derivative; ml I) adjacent to the anticodon of certain eukaryotic tRNA possibly helps maintaining the correct reading frame of the mRNA during the translation process. In double stranded RNA,inosine residues facilitate unwinding and consequently the degradation of the nucleic acid by endogeneous nucleases. An important question is how the different adenosine deaminases recognize their target nucleotides within RNA. The sequence and/or conformation (architecture) of the RNA around the modification-editing sites are important. It could also be that the site-specific adenosine deamination (A/I conversion) in GluR mRNA of mammalian brain depends on RNA recognition by proteins that specifically target the catalytic RNA adenosine deaminase to the editing site. This would be analogous to the site-specific cytosine deamination (C/U conversion) in the apolipoprotein B mRNA of mammalian intestine.